Swedish amyloid precursor protein mutation increases phosphorylation of eIf2α in vitro and in vivo

Swedish double mutation (KM670/671NL) of amyloid precursor protein (Swe-APP), a prevailing cause of familial Alzheimer's disease (FAD), is known to increase in AP production both in vitro and in vivo, but its underlying molecular basis leading to Alzheimer's disease (AD) pathogenesis remains to be elucidated, especially for the early phase of disease. We have confirmed initially that the expression of Swe-APP mutant transgene reduced cell viability via ROS production but this effect,was eliminated by an anti-oxidative agent, vitamin E. We also found that eukaryotic translation initiation factor-2 alpha (elf2 alpha), which facilitates binding of initiator tRNA to ribosomes to set on protein synthesis, was phosphorylated in cultured cells expressing Swe-APR This increase in phosphorylated elF2 alpha was also attenuated significantly by treatment with vitamin E. The finding that elF2 alpha became highly phosphorylated by increased production of A beta was substantiated in brain tissues of both an AD animal model and AD patients. Although an increase in A beta production would result in cell death eventually (in late-phase of the disease), the altered phosphorylation state of elf2 alpha evoked by A beta may account for the decreased efficacy of mRNA translation and de novo protein synthesis required for synaptic plasticity, and may consequently be one of molecular causes for impairment of cognitive functions exhibited in the early phase of AD patients. (c) 2007 Wiley-Liss, Inc.